Composition for controlling mood disorders in healthy individuals

ABSTRACT

The use of acetyl L-carnitine and its pharmacologically acceptable salts is disclosed for producing a composition suitable for controlling mood disorders mainly in young individuals who are not affected by permanent pathological CNS disturbances.

The present invention relates to the use of acetyl L-carnitine and itspharmacologically accetable salts for producing a composition suitablefor controlling mood disorders in individuals not presenting permanentpathological alterations of the central nervous system (CNS) byrestoring the normal balance of neurotransmitter levels.

For the purposes of the present invention what is meant by “mooddisorders” are those disorders which present as behavioural alterationsof a depressive or manic type and, in particular, those disorders thatpresent as oscillations between depressive and manic states alternatingin the same individual. According to the present invention, thesedisorders also include the so-called premenstrual syndrome and states ofbulimia.

Normal variations in mood (melancholy, mildly depressed states, anguishor joy and moderate excitement) constitute habitual aspects of dailylife and must be distinguished from the pathological fluctuations ofaffective disorders.

Nevertheless, increasingly wide oscillations in affective attitudes andin that complex series of behavioural reactions and expressions, whethertowards the self or towards external reality, which we definesynthetically as “mood”, would appear to affect an increasingly largepopulation, consisting mainly of young individuals. Though the extent ofsuch oscillations fails to reach the threshold of pathologicalrelevance, this phenomenon is beginning to have substantialrepercussions on important aspects of family life and on social andpersonal relations with profound consequences even of a socio-economicnature.

The main cause of this phenomenon probably has to do with the profoundchanges in lifestyle which have occurred, particularly with regard toyoung individuals, over a relatively short space of time.

Whereas, on the one hand, the opportunities for socialising (from traveland holidays even in far-off locations to attending public events andfrequenting public meeting places, such as discotheques, aimed mainly atattracting a youthful population) have increased enormously compared tothe past, amongst other things as a by-product of the boom in affluence,this phenomenon also presents worrying negative aspects such as theincreased use of beverages with a strong alcohol content and the everwider diffusion of psycho-active substances and of soft and hard drugs.

Set against the liberalisation of sexual habits and the increasinglywidespread use and greater safety of contraceptive methods is the fearof sexually transmitted diseases, the most notable, of course, beingAIDS, with its deterrent burden of anxiety which can have adverserepercussions on the normal expression of libido in both male and femalesubjects.

It is therefore hardly surprising that increasingly large numbers of theyounger population are suffering from mood disorders.

These disorders which have a tendency to become chronic, but whichexclude the precipitation of major or decidedly bipolar, cyclothymicdepression disorders, are currently classified as dysthymias (DSM IV,300.40) according to the definition provided by the authoritativeDiagnostic and Statistical Manual of Mental Disorders (DSM IV) publishedby the American Psychiatric Association.

In these dysthymic individuals, who present a reduced social functionalcapability due to the chronic nature of their disorders, and certainlynot as a result of the severity of their depressive or manicdisturbances, there are often associated disorders of eating habits,with lack of appetite or bulimia, insomnia or hypersomnia, asthenia andfatigue, and reduced self-esteem, concentration and decision-makingability.

The attempts made to date to treat the mood disorders described abovewith well-known tricyclic antidepressants such as imipramine,nortriptyline, desipramine, amitriptyline etc., have failed to yieldsatisfactory results, whereas, in younger subjects particularly, theirtroublesome side effects such as sedation, dry mouth, tremors, posturalvertigo, blurred vision, sweating and constipation are poorly tolerated.

It has now been found that acetyl L-carnitine and its pharmacologicallyacceptable salts constitute an effective means of treating theabove-described mood disorders essentially without presenting any of theside effects typical of tricyclic antidepressants.

The object of the present invention thus consists in the use of acetylL-carnitine or of one of its pharmacologically acceptable salts toproduce a composition suitable for controlling mood disorders inindividuals not presenting permanent pathological alterations of thecentral nervous system (CNS) by restoring the normal balance ofneurotransmitter levels.

It is important to note that, since the subjects who are to receive thecompositions of the present invention are essentially healthy and do notpresent fluctuations of pathological significance in their affective ormood disorders, the compositions of the invention may present themselvesnot only as pharmaceutical compositions, but also as health foods,medical foods or nutraceuticals, or as components of such products,containing other active ingredients, dietary supplements, vitamins,co-enzymes, mineral substances and the like in combination with acetylL-carnitine.

The compositions of the invention are formulated, as regards theirpresentation form, nature of the unit dose form, weight and so on, insuch a way as to favour administration of 500-3000 mg/day of acetylL-carnitine or a molar equivalent amount of one of its pharmacologicallyacceptable salts to subjects who need it, either in a single dose oraccording to a multidose administration regimen.

In cases in which the subject suffering from a mood disorder, as definedin the context of the invention described herein, is also a bulimic oroverweight subject (bulimia and depression often being associatedmanifestations in the same subject), the compositions may alsoadvantageously include an effective amount of 5-hydroxy-tryptophane(5-HTP) in addition to acetyl L-carnitine or one of itspharmacologically acceptable salts.

Compositions suitable for such subjects are those which, as a result oftheir presentation form, type of unit dose form, weight and so on,favour the administration to the subject of 500-1500 mg/day of acetylL-carnitine or a molar equivalent amount of one of its pharmacologicallyacceptable salts and 300-700 mg/day of 5-hydroxy-tryptophane.

The efficacy of acetyl L-carnitine for the treatment of mood disordersaccording to the invention has been demonstrated, amongst other things,by a clinical trial which will be described here below.

CLINICAL TRIAL

The selection of the patients for this trial consisted in a selection byexclusion, in which the medical history criterion was of paramountimportance, with exclusion of all patients presenting episodes of majordepression and cyclothymic manifestations classifiable as such on thebasis of the DMS criteria.

Subjects were therefore recruited whose mood disorders had beendominated by dysphoric manifestations for at least 4 years, classifiableas dysthymia (DMS IV) and a depressive, irritable, cyclothymicpersonality or temperament on the basis of DMS IV and AXIS II. A totalof 20 patients were selected, 12 males and 8 females, matching up to theabove-mentioned criteria, and with a mean age of 26±2 years. Sixpatients (males) also complained of diminished libido and episodes ofimpotence, while the 8 female patients complained of loss of libido andanorexia. Eight patients (4 males) reported an increased intake ofalcoholic beverages, without clinical complications, in the previous 8months (mean intake 142±15 g/day) and 6 patients (1 male) reportedbulimic episodes resulting in a mean weight gain of 2.1±0.5 kg over theprevious 6 months.

Each patient was recruited into the study after 3 repeated visits, atmonthly intervals, for the purposes of ruling out other concomitantpathologies or disorders according to DMS IV and AXIS II involvingdefinite abuse of psychotropic substances. The objective neurologicalexamination, current laboratory tests (SMA plus), ECG. BP and chestX-rays were all within normal limits.

None of the patients had been treated with SSRI or tricyclicantidepressants during the previous year. In the course of the monthpreceding the treatment with acetyl L-carnitine all treatmentsconsisting in administration of benzodiazepines during the daytime werediscontinued and only the administration of Lorazepam (2.5 mg) at 9 p.m.was allowed for all patients.

Each patient was administered acetyl L-carnitine 1 g per os twice daily(at breakfast- and lunch-time) for two months.

During the clinical interviews, at entry into the study, on day 45 ofadministration of acetyl L-carnitine and on day 90 (one month after theend of the treatment), patients were administered the followingstandardized rating scales: Hamilton Depression Rating Scale (HDRS),Hamilton Anxiety Rating Scale (HARS), Global Functional (or SocialAdaptation) Rating (GFR).

For the recording of alcohol intake, a self-administered scale was usedto record the alcohol-free days as a percentage of the total and thenumber of daily alcohol intakes, considering the intake of 10 grams as asingle intake, in the month preceding treatment, during the treatmentmonths and in the month following acetyl L-carnitine treatment.

The alcohol-free days during the two months of acetyl L-carnitinetreatment numbered 16±3 on average, whereas in the baseline conditionand in the month after treatment they numbered 6±2 and 8±2, respectively(F=13.13, p<0.05). The mean number of alcohol intakes was 6.1±2.1 asagainst 7.8±1.2 (F=5.27, p<0.05). All male patients reported thedisappearance of symptoms of impotence and diminished libido 15 daysafter the start of acetyl L-carnitine treatment.

The table shows the findings obtained with the rating scalesadministered. The laboratory tests performed at the end of treatmentyielded normal values; no significant changes as compared topre-treatment conditions were found in laboratory tests. BP and ECG.

The results of the clinical trial demonstrate that acetyl L-carnitinesignificantly reduces expression of the depressive behavioural componentin subjects suffering from dysthymic disorders. Reduction of thedepressive component is the basic aim of drug therapy in these patients,in that the various disorders of social adaptation, such as bulimia orintake of psychotropic substances, are largely subordinate components ofthe chronic character disturbance, which by definition is unresponsiveto the therapies commonly aimed at resolving major depressive orcyclothymic episodes.

Basal Day 45 Day 90 F P HDRS 13.9 ± 5.3  9.1 ± 4.8 12.8 ± 5.4 25.2 <0.01HARS 18.6 ± 3.8 12.8 ± 4.4 16.9 ± 5.0 24.3 <0.05 GFR 63.4 ± 6.6 75.3 ±7.9 67.7 ± 6.8 19.8 <0.05

The compositions of the invention can be obtained by mixing the activeingredient (acetyl L-carnitine or one of its pharmacologicallyacceptable salts, and, possibly, 5-HTP) with suitable excipients for theformulation of compositions which lend themselves to enteraladministration (particularly oral) or to parenteral administration(particularly by the intramuscular or intravenous routes). All suchexcipients are well known to pharmacy experts.

What is meant by pharmacologically acceptable salt of acetyl L-carnitineis any salt of acetyl L-carnitine with an acid that does not give riseto unwanted side effects. These acids are well known to pharmacyexperts.

Non-exclusive examples of such salts are chloride bromide, iodide, acidaspartate, acid citrate, tartrate and acid tartrate, acid phosphate,fumarate and acid fumarate, glycerophosphate, glucose phosphate,lactate, maleate and acid maleate, orotate, acid oxalate, acid sulphate,trichloroacetate, trifluoroacetate and methanesulphonate.

Here below are some examples of formulations in unit dosage form.

(a) Formulation for Tablets

One tablet contains:

Active ingredient acetyl L-carnitine Hcl 590 mg (equivalent to 500 mg ofacetyl L-carnitine, internal salt) Excipients Microcrystallinecellulose, polyvinylpyrrolidone, magnesium stearate, cellulose acetatephthalate, diethylphthalate, dimethicone.

(b) Formulation for Intravenous Injectable Ampoules

One lyophilized ampoule contains:

Active ingredient acetyl L-carnitine, internal salt 500 mg Excipientsmannitol One solvent ampoule contains: water for injections q.s. to 5ml.

(c) Formulation for Sachets

One sachet contains:

Active ingredient acetyl L-carninne Hcl 590 mg (equivalent to 500 mgacetyl L-carnitine, internal salt) Excipients precipitated silica,saccharin sodium, hydroxypropylcelluose, sodium bicarbonate, tonic water(1 × 1000), mannitol.

(d) Formulation for Extemporary Solution

One 12.316 g vial contains:

Active ingredient acetyl L-carnitine Hcl 12.0 g (equivalent to 10.17 gbase) Excipients methyl p-hydroxybenzoate, propyl p-hydroxybenzoate,polyvinylpyrrolidone.

(e) Formulation for Capsules (Acetyl L-carnitine +5-HTP)

Active ingredients acetyl L-carnitine, internal salt 250 mg 5-HTP 250 mgExcipients starch  20 mg mannitol  30 mg magnesium stearate  3 mg

What is claimed is:
 1. A composition, comprising: acetyl L-carnitine orits pharmacologically acceptable salt; an excipient; and5hydroxy-tryptophane.
 2. The composition of claim 1, wherein saidpharmacologically acceptable salt of acetyl L-carnitine is at least onesalt selected from the group consisting of acetyl L-carnitine chloride,bromide, iodide, acid aspartate, acid citrate, tartrate and acidtartrate, acid phosphate, fumarate, acid fumarate, glycerophosphate,glucose phosphate, lactate, maleate, acid maleate, orotate, acidoxalate, acid sulphate, trichloroacetate, trifluoroacetate andmethanesulphonate.
 3. The composition according to claim 1, wherein saidexcipient is selected from the group consisting of microcrystallinecellulose, polyvinylpyrrolidone, magnesium stearate, cellulose acetatephtalate, diethylphtalate and dimethicone.
 4. The composition accordingto claim 1, wherein said excipient is mannitol.
 5. The compositionaccording to claim 1, wherein said excipient is selected from the groupconsisting of precipitated silica, saccharin sodium, hydroxypropylcellulose, sodium bicarbonate, tonic water and mannitol.
 6. Thecomposition according to claim 1, wherein said excipient is selectedfrom the group consisting of methyl p-hydroxybenzoate, propylp-hydroxybenzoate and polyvinylpyrrolidone.
 7. The composition accordingto claim 1, further comprising at least one component selected from thegroup consisting of a nutraceutical, a dietary supplement, a vitamin, aco-enzyme and a mineral substance.
 8. The composition according to claim1, wherein said excipient is selected from the group consisting ofstarch, mannitol and magnesium stearate and combinations thereof.
 9. Thecomposition according to claim 1, further comprising at least onecomponent selected from the group consisting of a nutraceutical, adietary supplement, a vitamin, a co-enzyme and a mineral substance. 10.A method for treating a mood disorder, comprising: administering thecomposition according to claim 2 to a subject in need thereof, therebyrestoring a neurotransmitter level.
 11. The method according to claim10, wherein a dose is 500-1500 mg/day of acetyl L-carnitine or a molarequivalent of its pharmaceutically acceptable salt and 300-700 mg/day of5-hydroxy-tryptophane.
 12. The method according to claim 10, wherein themood disorder is a depressive or manic behavioral alteration.
 13. Themethod according to claim 10, wherein a depressive state and a manicstate alternate in said subject.
 14. The method according to claim 10,wherein said subject is bulimic, overweight or both.
 15. A method fortreating a mood disorder, comprising: administering the compositionaccording to claim 1 to a subject in need thereof, thereby restoring aneurotransmitter level.
 16. The method according to claim 15, wherein adose is 500-3000 mg/day of acetyl L-carnitine or a molar equivalent ofits pharmaceutically acceptable salt.
 17. The method according to claim15, wherein the mood disorder is a depressive or manic behavioralalteration.
 18. The method according to claim 15, wherein a depressivestate and a manic state alternate in said subject.
 19. The methodaccording to claim 15, wherein a Hamilton Depression Rating Scale ofsaid subject is decreased from a value of 13.9±5.3 before saidadministering to a value of 9.1±4.8 after said administering.
 20. Themethod according to claim 15, wherein a Hamilton Anxiety Rating Scale ofsaid subject is decreased from a value of 18.6±3.8 before saidadministering to a value of 12.8±4.4 after said administering.
 21. Themethod according to claim 15, wherein a Global Function Rating of saidsubject is increased from a value of 63.4±6.6 before said administeringto a value of 75.3±7.9 after said administering.
 22. The methodaccording to claim 15, wherein a Hamilton Depression Rating Scale ofsaid subject is decreased from a value of 13.9±5.3 before saidadministering to a value of 12.8±5.4 after said administering.
 23. Themethod according to claim 15, wherein a Hamilton Anxiety Rating Scale ofsaid subject is decreased from a value of 18.6±3.8 before saidadministering to a value of 16.9±5.0 after said administering.
 24. Themethod according to claim 15, wherein a Global Function Rating of saidsubject is increased from a value of 63.4±6.6 before said administeringto a value of 67.7±6.8 after said administering.
 25. A method,comprising: admixing acetyl L-carnitine or its pharmacologicallyacceptable salt with an excipient and with 5-hydroxy-tryptophane,thereby obtaining a composition.
 26. The method of claim 25, whereinsaid pharmacologically acceptable salt of acetyl L-carnitine is at leastone salt selected from the group consisting of acetyl L-carnitinechloride, bromide, iodide, acid aspartate, acid citrate, tartrate andacid tartrate, acid phosphate, fumarate, acid fumarate,glycerophosphate, glucose phosphate, lactate, maleate, acid maleate,orotate, acid oxalate, acid sulphate, trichloroacetate, trifluoroacetateand methanesulphonate.
 27. The method of claim 25, wherein saidexcipient is selected from the group consisting of microcrystallinecellulose, polyvinylpyrrolidone, magnesium stearate, cellulose acetatephtalate, diethylphtalate, dimethicone, precipitated silica, saccharinsodium, hydroxypropyl cellulose, sodium bicarbonate, tonic water,mannitol, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate.